Colistin-induced acute kidney injury via zinc Dyshomeostasis-triggered GSDMD-executed Pyroptosis

  • Int Immunopharmacol. 2026 Jan 1;168(Pt 1):115768. doi: 10.1016/j.intimp.2025.115768.
Qinjie Yang  1 ,  Kun Liu  1 ,  Rongping Zhu  1 ,  Xiaocong Zuo  2 ,  Yueliang Xie  3
Affiliations
  • 1. Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
  • 2. Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China; Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
  • 3. Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China; Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. Electronic address: [email protected].
PMID: 41176907 DOI: 10.1016/j.intimp.2025.115768
Abstract

Colistin, a formulation of polymyxins and the last-line agent against multidrug-resistant Gram-negative infections, has its clinical utility limited by acute kidney injury (AKI) with unclear pathogenesis. Pyroptosis, a proinflammatory programmed cell death pathway, contributes significantly to tubular injury in drug-induced AKI. However, its role in colistin-induced AKI is unknown. Emerging evidence implicates dysregulated zinc homeostasis in promoting Pyroptosis. Here, we report that colistin sulfate induces intracellular zinc ion overload in murine kidneys and renal tubular epithelial cells. This zinc dyshomeostasis augmented gasdermin D (GSDMD)-executed Pyroptosis, thereby axacerbating colistin-induced AKI progression. Critically, chelation of intracellular zinc ion attenuated Pyroptosis and mitigated renal damage. Our findings identify zinc dyshomeostasis-driven Pyroptosis as a pathogenic mechanism in colistin-associated nephrotoxicity, revealing a potential therapeutic approach for preventing colistin-induced AKI.

Keywords
Acute kidney injury; Colistin; Pyroptosis; Zinc homeostasis.
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